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Robert E MacLaren, Kanmin Xue, Alun R Barnard, Maria In?s Patrício, Thomas L Edwards, Susan Downes, Andrew Lotery, Graeme Black, Andrew Webster, Jasleen K Jolly, Miguel C Seabra; Retinal Gene Therapy for Choroideremia in a Multicenter Dose Escalation Phase I/II Clinical Trial. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1195. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Choroideremia is a currently incurable X-linked retinal degeneration. Here we report the final results of a non-randomised phase I/II clinical trial assessing retinal gene therapy using an adeno-associated virus serotype 2 (AAV2) vector expressing the choroideremia transgene (REP1) at the 2-year primary endpoint.
In total 14 patients were recruited, 12 of whom received subretinal gene therapy as per protocol without complications. Doses ranged from 6x109 to 1x1011 genome particles of AAV2.REP1. The primary outcome measure of safety and efficacy was visual acuity at 2 years.
Over the entire group of 14 patients, by 2 years the median visual acuity improved by 4.5 letters in the treated eyes compared with a loss of 1.5 letters in the untreated eyes (p=0.04). For the 12 patients receiving gene therapy without complications, the treated eyes had gained 5.5 letters above their baseline level by 2 years (p=0.02). Compared to the untreated eyes, by 2 years this represented a median 4.5 letter gain in favour of the eyes receiving gene therapy (p=0.001). By this time, 6 of the 12 treated eyes had gained more than one line of vision (>5 letters), compared with none of the 12 untreated eyes. The adverse events in the two patients who were treated off protocol related to surgically induced retinal thinning with under-dosing in one case and inflammation (vitritis and choroiditis) in the other. The complications in these two patients led to visual acuity losses of 15 and 14 letters, respectively by 2 years. Changes to the protocol were made midway through the trial to reduce the chance of these complications occurring in future. These included introduction of an automated subretinal injection system, intra-operative OCT and an extended course of post-operative immune suppression. At the last follow up (range 2-5 years), visual acuity had been maintained or increased in all 12 study eyes that had received gene therapy as per protocol, compared with only 4 of the 12 untreated eyes. This was equivalent to a mean difference of 16.0 letters (>3 lines) between eyes.
In general, retinal gene therapy for choroideremia appears to be safe. It sustained and improved visual acuity in a cohort of predominantly late stage patients in whom rapid visual acuity loss would ordinarily be predicted. Longer term follow-up in a fully randomised clinical trial is needed to confirm these observations.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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